After the sins of Eve (and Adam) in the Garden of Eden, Genesis 3:16 presents her divine punishment: “To the woman He said, ‘I will greatly increase your pangs and your childbearing; in pain you shall bear children.’”
In modern society, women’s pain during labor has been significantly reduced with regional anesthetics such as epidurals and spinals, inhaled nitrous oxide, and intravenous or intramuscular opioids. But how about during pregnancy? Many gynecologists/obstetricians have discouraged such women from taking all painkillers.
A study at Ben-Gurion University of the Negev (BGU) in Beersheba has provided definitive safety data on painkiller use during pregnancy.
Based on an analysis of over 264,000 pregnancies, it showed that non-steroidal anti-inflammatory drugs (NSAIDs – ibuprofen, commercially known as Advil/Nurofen) are safe during the first three months and confirm the safe use of paracetamol (Acamol/Tylenol) throughout pregnancy, including in the last trimester.
It offered much-needed clarity to women worldwide regarding the safety of these common painkillers; they do not increase the risk of birth defects.
Articles were published in two journals: PLOS Medicine under the title “First-trimester nonsteroidal anti-inflammatory drugs exposure and risk of major congenital malformations: A retrospective register-based cohort study” and “Paracetamol exposure during pregnancy, the risk of major congenital malformations, and perinatal and postnatal outcomes: a population-based cohort study” in Human Reproduction Open.
“At first glance, raw data might suggest a slight increase in birth defects among women who took these medications,” explained Dr. Sharon Daniel, a senior pediatrician and head of Innovation at Clalit Healthcare Services’ southern district, and an epidemiologist and biostatistician at BGU.
“However, our analysis revealed that the risk was actually tied to the mother’s underlying condition – such as a high fever that can itself pose risks because prolonged high body temperature and inflammation, possibly affecting fetal development and pregnancy outcomes, infection, or chronic illness – rather than the painkillers themselves,” he continued.
They were based on 20 years of comprehensive clinical data conducted through the siPREG (Southern Israeli Pregnancy Registry), an exceptionally accurate, detailed, and reliable data initiative that tracks maternal and fetal health outcomes to answer critical questions for global medicine.
The researchers analyzed all pregnancies documented at Soroka University Medical Center between 1998 and 2018 that ended either in birth or pregnancy termination due to suspected fetal abnormalities. Of the total, over 20,000 women took NSAIDs during pregnancy.
“Our results suggest that paracetamol use throughout pregnancy is not independently associated with adverse perinatal outcomes, and that commonly used NSAIDs in early pregnancy are not associated with an increased risk of major congenital malformations,” Daniel said.
“Overall, this supports focusing on treating the underlying condition when medically indicated rather than avoiding treatment due to concerns about the medications. I hope these findings help shift the discussion toward more evidence-based reassurance,” he added.
They found no link between first-trimester NSAID use and malformations in any major organ system, including the heart and central nervous system. One of the most common medications used globally, paracetamol, was found to have no involvement with birth defects, stillbirth, or low birth weight. Third-trimester use of paracetamol showed no increased risk of newborn renal failure or heart-related complications.
Although the raw rate of birth defects was slightly higher among exposed pregnancies (8.2% vs 7.0%), after adjusting for factors such as fever, inflammatory diseases, pain, maternal background characteristics, and chronic illnesses, the apparent association disappeared.
Researchers concluded that the increased risk was mainly explained by the underlying conditions requiring treatment rather than by the medications themselves.
There were no higher risks than the norm for defects or abnormalities, including in the cardiovascular system, musculoskeletal system, central nervous system, digestive system, and urinary system.
The second study focused on acetaminophen, the most commonly used medication worldwide for pain and fever reduction. Recent concerns suggested that acetaminophen use during pregnancy might be linked to adverse pregnancy outcomes.
Although the raw rate of birth defects appeared slightly higher among exposed pregnancies (7.9% vs. 6.9%), after statistical adjustment for pregnancy characteristics and medical conditions, researchers found no independent association between acetaminophen exposure and birth defects, he said.
“We expected the associations to weaken after rigorous adjustment, but we were surprised by how consistently reassuring the findings remained across multiple analyses, outcomes, and sensitivity tests,” Daniel told The Jerusalem Post. “Pregnant women should contact their doctor, especially if the fever is high, persistent, or accompanied by other symptoms. Fever is often a sign of an underlying condition that may require evaluation and treatment.
Previous studies have shown that maternal fever itself is associated with adverse pregnancy outcomes and complications, which is why timely assessment and management during pregnancy are important.
“Fever, infection, pain, and inflammation are not harmless,” he stressed. “One important message from our work is that the underlying illness may be more important than the medication used to treat it.”
Pregnant women should not blame themselves for taking medically indicated treatment, he went on.
“Decisions should be based on evidence and medical advice rather than fear or guilt,” he said. “When these medications are used appropriately for clear clinical indications, there is no reason for added anxiety based on the outcomes we studied. At the same time, as with any medication in pregnancy, use should remain guided by clinical judgment and existing recommendations.”
Asked why there were concerns about paracetamol in recent years, Daniel explained that “several observational studies reported links between prenatal paracetamol exposure and outcomes such as ADHD, autism spectrum disorder, and other neurodevelopmental conditions.
“In addition, biological concerns were raised because paracetamol is sometimes used in newborns, particularly premature infants, to help close a patent ductus arteriosus – a blood vessel that normally closes after birth but sometimes remains open.
“Because of this effect, some researchers and clinicians had questioned whether prenatal exposure to paracetamol might also affect the fetal cardiovascular system.”
The team found no evidence that paracetamol exposure during pregnancy was independently associated with adverse outcomes: “The question of long-term neurodevelopmental outcomes was not addressed in their research and remains an important area of inquiry that should be examined in studies specifically designed to evaluate them.
“NSAIDs are generally contraindicated in the third trimester due to concerns about premature closure of this artery and effects on fetal renal function. Current recommendations regarding NSAID use later in pregnancy remain unchanged,” Daniel said.
Research could influence pregnancy guidelines
The team found no fundamental differences between Jewish and Bedouin populations in the Negev. Daniel believes that the new findings could influence international pregnancy guidelines in time, with further support research, when evidence accumulates and is replicated across different settings and populations.
“We plan to use the siPREG registry to study other medications used during pregnancy because it allows us to study many medications and exposures that are difficult to evaluate using other research designs,” he added.
To ensure the findings were absolutely accurate, the team developed a “sensitivity analysis” to account for the reality of unreported over-the-counter drug use.
“We had to ensure that ‘real-world’ habits didn’t skew our results,” concluded co-author Dr. Ariel Hassidim. “We showed that the volume of unreported use would have to be impossibly high.”